EP2717885B1 - Antiinfective composition - Google Patents
Antiinfective composition Download PDFInfo
- Publication number
- EP2717885B1 EP2717885B1 EP12726137.8A EP12726137A EP2717885B1 EP 2717885 B1 EP2717885 B1 EP 2717885B1 EP 12726137 A EP12726137 A EP 12726137A EP 2717885 B1 EP2717885 B1 EP 2717885B1
- Authority
- EP
- European Patent Office
- Prior art keywords
- hydroxymethyl
- glycosaminoglycan
- group
- glycosaminoglycans
- containing glycosaminoglycan
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Classifications
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- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- C08B37/003—Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
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- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0069—Chondroitin-4-sulfate, i.e. chondroitin sulfate A; Dermatan sulfate, i.e. chondroitin sulfate B or beta-heparin; Chondroitin-6-sulfate, i.e. chondroitin sulfate C; Derivatives thereof
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- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0072—Hyaluronic acid, i.e. HA or hyaluronan; Derivatives thereof, e.g. crosslinked hyaluronic acid (hylan) or hyaluronates
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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- C08B37/006—Heteroglycans, i.e. polysaccharides having more than one sugar residue in the main chain in either alternating or less regular sequence; Gellans; Succinoglycans; Arabinogalactans; Tragacanth or gum tragacanth or traganth from Astragalus; Gum Karaya from Sterculia urens; Gum Ghatti from Anogeissus latifolia; Derivatives thereof
- C08B37/0063—Glycosaminoglycans or mucopolysaccharides, e.g. keratan sulfate; Derivatives thereof, e.g. fucoidan
- C08B37/0075—Heparin; Heparan sulfate; Derivatives thereof, e.g. heparosan; Purification or extraction methods thereof
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C08L5/08—Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
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- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
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- C08L2205/02—Polymer mixtures characterised by other features containing two or more polymers of the same C08L -group
Definitions
- the present invention relates to the use of glycosaminoglycans containing hydroxymethyl groups, such as, in particular, hydroxymethyl-hyaluronic acid, for the treatment and prevention of infectious or malignant diseases, in particular of the skin or the mucous membranes.
- the invention also relates to a production process for glycosaminoglycans modified with hydroxymethyl groups.
- Infectious diseases are diseases caused by pathogens such as viruses, bacteria or fungi that show a broad spectrum of time courses and symptoms that are often specific to the pathogen. Infection occurs when an organism comes into contact with a pathogen, the pathways of infection being characteristic of the disease and its pathogen. For many pathogen-related diseases, medicine has specific antidotes ready, such as antibiotics against bacteria, antimycotics against fungi and antivirals against viruses. There is also the possibility of a preventive vaccination against some pathogens.
- Secondary infections represent a further problem, in which, in addition to an initially present infection (primary infection), another infection with another pathogen occurs. Such a further infection after a primary infection can pose great problems for the immune system and also make therapy and medication more difficult. Secondary infections with viral, bacterial or fungal diseases are of particular importance if the primary infection is accompanied by a weakening of the immune system. It would therefore be desirable to provide active ingredients that enable different pathogens to be combated at the same time.
- WO 2005/067944 describes the use of hyaluronic acid for the treatment of inflammatory diseases, in particular skin or mucous membrane diseases.
- glycosaminoglycan derivatives which have been modified with hydroxymethyl groups have an excellent anti-infective effect against different types of pathogens. It was found that this anti-infective effect is due to the presence of hydroxymethyl groups on the glycosaminoglycan.
- the invention thus provides a hydroxymethyl group-containing glycosaminoglycan for use in the treatment or prevention of infectious or malignant diseases, as defined in the appended claims.
- Glycosaminoglycans are linear polysaccharides made up of repeating modified disaccharides.
- the individual disaccharide units consist of a uronic acid that is 1 ⁇ 3 glycosidically linked to an amino sugar, such as N-acetyl-glucosamine.
- the disaccharide units of the chains themselves are linked 1 ⁇ 4 glycosidically.
- Glycosaminoglycans are components of many biological macromolecules and form the framework of many fiber-forming substances. Examples of glycosaminoglycans are hyaluronic acid, heparin, chondroitin sulfate, dermatan sulfate and keratan sulfate. According to the invention, chitosamine and poly-N-acetyl-glucosamine are also understood as glycosaminoglycans.
- the glycosaminoglycan is preferably a hyaluronic acid.
- Glycosaminoglycans are usually obtained from protein-containing biological tissues. For example, the isolation of hyaluronic acid from cockscomb or streptococci is known. Natural heparins are extracted from pig small intestinal mucosa, among other things. Chondroitin sulfate is largely obtained from the cartilage tissue of cattle, pigs and sharks. In addition, glycosaminoglycans can be produced from genetically modified host organisms, e.g. bacterial cells.
- hyaluronic acid and derivatives thereof are used for viscoelastic supplementation of joints in osteoarthritis, for filling tissues, especially the dermis, as so-called "dermal fillers” and for treating inflammatory diseases of the skin and mucous membranes.
- skin fillers for treating inflammatory diseases of the skin and mucous membranes.
- WO 2005/067944 the treatment and prophylaxis of diseases of the skin and mucous membranes caused by herpes and papillomaviruses.
- glycosaminoglycan derivatives in which one or more amino groups are substituted with hydroxymethyl groups, have an anti-infective effect and are also suitable for the treatment of malignant diseases of body surfaces.
- the disaccharide units, from which glycosaminoglycans are built consist, as mentioned above, of a uronic acid and an amino sugar.
- a hydroxymethyl group is bonded to one or more nitrogen atoms of amino groups.
- the glycosaminoglycans containing hydroxymethyl groups according to the invention thus have characteristic substituents —N (R) —CH 2 OH, where R can be any radical, in particular H or acetyl. These are preferably bound to the aminosugars of the disaccharide units of the glycosaminoglycan.
- glycosaminoglycans which contain the amino sugar N-acetylglucosamine
- the N-acetyl group is preferably substituted with a hydroxymethyl group.
- Characteristic for these hydroxymethyl group-containing glycosaminoglycans in the context of the invention are -N (acetyl) -CH 2 OH groups. These compounds surprisingly show a particularly high anti-infective effect.
- Infectious diseases within the meaning of the present invention are caused by herpes or papillomavirus. Infectious diseases that are not caused by papilloma or herpes viruses are also described. Infectious diseases which according to the invention can be treated or prevented by means of glycosaminoglycans containing hydroxymethyl groups are infectious skin or mucous membrane diseases.
- the mucous membrane includes in particular the surfaces of the gastrointestinal tract, the urogenital tract, the lungs and hollow organs.
- infectious diseases can be treated, which are primarily viral infectious diseases with subsequent superinfection by bacteria and / or fungi, preferably those species that are resistant to common antibiotics.
- viruses DNA and RNA viruses come into question; in the case of bacteria, they are pathogenic, gram-negative and gram-positive, anaerobically or aerobically growing bacteria;
- the agent according to the invention is also suitable for the treatment of malignant diseases of the body surfaces, in particular basal cell carcinoma of the epidermis and its precursors such as solar keratosis or Bowen's disease. This is injected, for example, with a gel-like preparation of the agent according to the invention and then grows to the surface, where it is repelled. It is also described that other malignant diseases can be treated adjuvantly with the agent according to the invention, e.g. B. peritoneal carcinosis by means of a solution instilled into the abdominal cavity.
- glycosaminoglycans used according to the invention are hyaluronic acid substituted on amino groups with hydroxymethyl, heparin, chondroitin sulfate, chitosamine and poly-N-acetylglucosamine, hyaluronic acid being particularly preferred.
- one or more amino groups are substituted with hydroxymethyl groups.
- the degree of hydroxymethylation is preferably in the range from 200: 1 (0.5%) to 1: 1 (100%), preferably 100: 1 (1%) to 10: 1 (10%).
- the anti-infective effect of glycosaminoglycans increases.
- hydroxymethyl-hyaluronic acid it could be shown in vitro that the virocidal effect in particular is increased.
- a particularly preferred embodiment of the Invention is hydroxymethyl hyaluronic acid for use in the treatment or prevention of infectious Diseases, especially viral diseases, caused by herpes or papillomavirus. Also described are bacterial or fungal diseases or diseases that are not caused by herpes or papillomaviruses.
- the hydroxymethyl group-containing glycosaminoglycans according to the invention have improved tissue compatibility. They remain at their site of action for longer, and the length of stay can be controlled through the choice of the molecular weight of the glycosaminoglycan used and its degree of crosslinking. For example, depending on its molecular weight and degree of crosslinking, hydroxymethyl-hyaluronic acid remains at the site of action for about 24 hours to six months.
- the modified glycosaminoglycans according to the invention have the advantage that the pathogens do not develop any resistance and that they have an expanded spectrum of pathogens. Degradation and excretion take place naturally via specific enzymes.
- glycosaminoglycans containing hydroxymethyl groups are suitable for the purposes of the invention both in uncrosslinked and in crosslinked form or as mixtures.
- Uncrosslinked or crosslinked hyaluronic acid or mixtures thereof are particularly preferably used.
- Uncrosslinked glycosaminoglycans are preferably selected from (i) long-chain glycosaminoglycans with an average molecular weight (weight average) of at least 200 kD and (ii) short-chain glycosaminoglycans with a weight average molecular weight of up to 50 kD or mixtures thereof.
- Crosslinked glycosaminoglycans can, for example, be covalently or non-covalently crosslinked.
- the crosslinked glycosaminoglycans can be prepared in a known manner.
- the covalent crosslinking generally takes place by crosslinking with bifunctional reactive agents, such as diepoxyoctane, BDDE, divinyl sulfone, glutaraldehyde or carbodiimide, via bifunctional amino acids, e.g. lysine, protamine or albumin.
- cross-links can also be established via an amide, ester or ether bond.
- glycosaminoglycans are ethylene glycol or 1-4-butanediol diglycidether, divinyl sulfone, photocrosslinking reagents such as ethyl eosin, hydrazides such as bishydrazide, trishydrazide and polyvalent hydrazide compounds.
- glycosaminoglycans which are intra- and / or intermolecularly esterified or crosslinked with hexamethylenediamine can also be used.
- Particularly preferred is non-covalent cross-linking using polyvalent metal ions such as iron, copper, zinc, calcium, magnesium, manganese, barium and other chelating metal ions.
- the molecular weight is important, and in the case of crosslinked glycosaminoglycans the degree of crosslinking, which is, for example, in the range from 0.1 to 10%, without being limited thereto.
- the degree of crosslinking which is, for example, in the range from 0.1 to 10%, without being limited thereto.
- long-chain glycosaminoglycans a lower degree of crosslinking is sufficient to obtain a gel-like matrix
- short-chain glycosaminoglycans a higher degree of crosslinking is required in order to obtain comparable properties.
- glycosaminoglycan according to the invention can be used both in human medicine and in veterinary medicine, for example for the treatment of domestic animals or farm animals.
- the administration of the hydroxymethyl group-containing glycosaminoglycan can in principle in any manner if this is suitable for the treatment of the respective disease.
- Systemic or local administration is conceivable. In many cases, local administration takes place in the area of the diseased part of the body.
- An inventive glycosaminoglycan containing hydroxymethyl groups can be present for use in the treatment of infectious diseases in the form of a pharmaceutical composition in which one or more glycosaminoglycans containing hydroxymethyl groups in an amount of preferably 0.01 to 20 percent by weight, based on the total pharmaceutical composition, in particular are contained in an amount of 0.01 to 5 percent by weight and particularly preferably in an amount of 0.01 to 1 percent by weight.
- compositions according to the invention can contain as pharmaceutical auxiliaries, e.g. agents for pH adjustment, stabilizers, antioxidants, solubilizers, penetration-promoting agents, preservatives and / and gelling agents, as are usually used in such compositions. They are used in the amounts customary in such preparations.
- auxiliaries e.g. agents for pH adjustment, stabilizers, antioxidants, solubilizers, penetration-promoting agents, preservatives and / and gelling agents.
- the pharmaceutical compositions according to the invention can optionally also contain one or more further pharmaceutical active ingredients which are compatible with the glycosaminoglycan derivative.
- further active ingredients are active ingredients for the therapy of skin diseases (dermatoses), antimycotics, antibiotics (e.g. gentamycin, vancomyzin, penicillin or cephalosporin), sulfonamides, disinfectants, hormones (e.g. corticoids) and hormone derivatives (e.g. cortisol), local anesthetics (e.g.
- vasoactive substances for vascular constriction vascular constriction (avoidance of Bleeding), adrenaline, enzymes (such as hyaluronidase), interleukins, growth factors (e.g. EGF, PDGF or / and IGF), vitamins (e.g. vitamin D), skin care products and / or blood circulation-promoting (hyperaemic) agents.
- the further active ingredients can optionally be associated with the glycosaminoglycan, for example through covalent or non-covalent interactions.
- additives such as divalent or trivalent metal ions, which can have a crosslinking and stabilizing effect through gelation and which, on the other hand, can also accelerate the breakdown of the effective glycosaminoglycans.
- glycosaminoglycans are naturally degraded by a large number of different enzymes or by oxygen radicals.
- Hyaluronic acid is broken down by hyaluronidases or oxygen radicals. Therefore, additives that inhibit enzymes such as hyaluronidase (heparin, indometazine and / or salicylates) and those that prevent oxidative degradation in the tissue as so-called radical scavengers (vitamins A, E and / or C) are also of importance.
- a mixture of long-chain glycosaminoglycans ( ⁇ 200 kD) with short-chain glycosaminoglycans (e.g. hexamers of the repetitive disaccharide units or larger units up to 50 kD) or mixtures of the aforementioned with cross-linked glycosaminoglycans is used to treat or prevent infectious diseases .
- the mixture creates viscous injectable preparations, which are preferably introduced intradermally with injection cannulas or by injection over a large area at the border of the dermoepidermal transition. The placement of individual wheals is also suitable according to the invention.
- the known local anesthetics can be added to the injectable glycosaminoglycan preparations to minimize the painfulness of the puncture.
- Another particularly preferred embodiment are mixtures of crosslinked and non-crosslinked glycosaminoglycans.
- the preparations according to the invention can also be used extremely effectively by pressure injection. This procedure is characterized by extensive freedom from pain.
- compositions according to the invention of the active ingredient are aqueous solutions or emulsions for intravenous administration or for instillation into body cavities or hollow organs.
- the preparations according to the invention can also be applied topically, i.e. superficially, to the skin in the form of ointments, creams, lotions, gels, sprays, tinctures, shampoos, and occlusive films.
- a special preparation form within the meaning of the invention is a dry glycosaminoglycan preparation in the form of a powder, which is used in particular for the treatment of weeping eczema.
- the invention also relates to the introduction of the active ingredients in microencapsulated form or in the form of liposomes. As far as mucous membranes of the respiratory tract are affected by an infectious disease, treatment with the glycosaminoglycans according to the invention containing hydroxymethyl groups can also be carried out using an aerosol as an inhalation solution.
- a composition according to the invention can be produced in a generally known manner which is customary per se for the production of such compositions.
- the order in which the individual components are mixed is generally not critical.
- compositions according to the invention as well as the nature (e.g. viscosity, Degree of cross-linking, active ingredient content etc.) depend in particular on the type and severity of the disease as well as on the age of the patient and the location and type of application, e.g. the condition and sensitivity of the affected parts of the body. If the compositions according to the invention are administered in the form of preparations that can be applied topically, the administration generally corresponds to the conditions customary for such compositions.
- the type of treatment and the frequency of application depends in particular on the individual response of the person to be treated.
- Gels or solutions are preferably applied at intervals of several days up to 1 or 2 months, in particular about 1-2 weeks.
- the invention also includes mixtures of a glycosaminoglycan containing hydroxymethyl groups with other glycosaminoglycans in crosslinked and / and non-crosslinked form.
- a glycosaminoglycan containing hydroxymethyl groups with other glycosaminoglycans in crosslinked and / and non-crosslinked form.
- Mixtures of hyaluronic acid containing hydroxymethyl groups and heparin are preferred.
- Mixtures of hyaluronic acid containing hydroxymethyl groups and positively charged glycosaminoglycans such as chitosamine are also preferred.
- the glycosaminoglycan starting product in step (i) is preferably Hyaluronic acid, heparin, chondroitin sulfate, chitosamine or poly-N-acetylglucosamine are used.
- the glycosaminoglycan in step (i) is isolated from a biological source or obtained biotechnologically, in particular from cockscomb or bacteria such as B. subtilis or streptococcal cultures.
- the glycosaminoglycan can be obtained from a biological source or from bacteria in the presence of formaldehyde or another hydroxymethyl group donor.
- the purified glycosaminoglycan from step (i) is then available, for example, as an aqueous solution, as a precipitate or as a hydrogel.
- step (ii) the glycosaminoglycan is then substituted with hydroxymethyl groups by chemical treatment.
- Step (ii) can be carried out together with step (i) or afterwards.
- Step (ii) can comprise, for example, the reaction of the glycosaminoglycan with formaldehyde or an agent which releases formaldehyde under the reaction conditions, such as taurolidine.
- a preferred method of introducing hydroxymethyl groups into the glycosaminoglycan e.g. hyaluronic acid
- taurolidine e.g. hyaluronic acid
- taurolidine e.g. hyaluronic acid
- the glycosaminoglycan modified with hydroxymethyl groups can then be purified in a further step (iii). Excess formaldehyde or residues of formaldehyde-releasing reagents from step (ii) are removed.
- the purification can, for example, by precipitation with, for example, alcohols or salts, by chromatography processes, dialysis processes, vacuum extraction and / or Freeze-drying can be carried out.
- a further step (iv) is then optionally carried out, in which the glycosaminoglycan substituted with hydroxymethyl groups is crosslinked.
- the crosslinking can also be carried out first and then the introduction of hydroxymethyl groups.
- the crosslinking can, as described above, take place according to methods known in the prior art.
- crosslinking takes place in step (iv) with one or more further glycosaminoglycans, which can optionally themselves be substituted on amino groups with hydroxymethyl groups.
- further glycosaminoglycans optionally modified with hydroxymethyl groups are heparin, chondroitin sulfate, chitosamine and poly-N-acetylglucosamine.
- a glycosaminoglycan containing hydroxymethyl groups is then combined with one or more further active ingredients and / or additives. Examples of such further active ingredients and additives are explained above.
- Another aspect of the invention relates to a combination of hydroxymethyl group-containing glycosaminoglycan with taurolidine, for example with a taurolidine solution, for example a 1-2% (w / v) taurolidine solution.
- Hyaluronic acid is preferably used as the glycosaminoglycan, the molecular weight of the hyaluronic acid being, for example, between 100,000 and 10,000,000 Daltons.
- a composition according to the invention can preferably be stored in gas-tight packaging, such as a glass syringe, and is characterized by an increased anti-infective and prolonged effect as well as improved tissue compatibility.
- HA obtained by fermentation from Streptococcus equi is dissolved in 2% taurolidine solution and kept at 40 ° C. for 12 hours. Thereafter, excess liquid is separated off by filtration and remaining liquid is removed by vacuum drying.
- the product obtained is then dissolved in physiological NaCl solution and the pH of the solution is adjusted to 10 with 1% NaOH.
- BDDE is then added to a concentration of 0.2%.
- the mixture is incubated at 40 ° C. for 4 hours.
- the pH of the batch is then adjusted to 7.4 with Na acetate and kept at 70 degrees Celsius for a further 24 hours. After cooling to room temperature, the batch can be further processed into the anti-infective end product, eg eye gel.
- Streptococcus equi species are grown in fermenters in a CO 2 enriched anaerobic atmosphere. After growth or reproduction has ended, formaldehyde is added in concentrated form to the nutrient solution so that the bacteria die.
- the solution is then centrifuged and the supernatant drawn off.
- the material obtained is mixed with dilute NaOH and shaken for 4 hours.
- the solution is then neutralized and ultrafiltered.
- the received Solution can be treated with alcohol and the dissolved HA precipitated and dried. There is thus a product according to the invention which can be further processed depending on the intended application.
- 100 ml of a 2% hyaluronic acid solution are mixed with 100 ml of a 2% taurolin solution and stored in a glass bottle in the absence of air. If necessary, the solution can be instilled into the abdominal cavity or the urinary bladder through a tube or catheter system.
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Description
Die vorliegende Erfindung betrifft die Verwendung von Hydroxymethylgruppen-enthaltenden Glycosaminoglycanen, wie insbesondere Hydroxymethyl-Hyaluronsäure, zur Behandlung und Vorbeugung infektiöser bzw. maligner Erkrankungen, insbesondere der Haut oder der Schleimhäute. Gegenstand der Erfindung ist außerdem ein Herstellungsverfahren für mit Hydroxymethylgruppen modifizierte Glycosaminoglycane.The present invention relates to the use of glycosaminoglycans containing hydroxymethyl groups, such as, in particular, hydroxymethyl-hyaluronic acid, for the treatment and prevention of infectious or malignant diseases, in particular of the skin or the mucous membranes. The invention also relates to a production process for glycosaminoglycans modified with hydroxymethyl groups.
Infektiöse Erkrankungen sind durch Erreger wie Viren, Bakterien oder Pilze hervorgerufene Erkrankungen, die ein breites Spektrum von zeitlichen Verläufen und Symptomen zeigen, die für den Erreger oftmals spezifisch sind. Die Infektion erfolgt durch Kontakt eines Organismus mit einem Krankheitserreger, wobei die Infektionswege charakteristisch für die Erkrankung und deren Erreger sind. Für viele erregerbedingte Krankheiten hält die Medizin spezifische Gegenmittel bereit, wie Antibiotika gegen Bakterien, Antimykotika gegen Pilze und Virostatika gegen Viren. Gegen einige Erreger besteht zudem die Möglichkeit einer vorbeugenden Impfung.Infectious diseases are diseases caused by pathogens such as viruses, bacteria or fungi that show a broad spectrum of time courses and symptoms that are often specific to the pathogen. Infection occurs when an organism comes into contact with a pathogen, the pathways of infection being characteristic of the disease and its pathogen. For many pathogen-related diseases, medicine has specific antidotes ready, such as antibiotics against bacteria, antimycotics against fungi and antivirals against viruses. There is also the possibility of a preventive vaccination against some pathogens.
Noch heute sind jedoch manche infektiöse Erkrankungen nicht heilbar. Zudem besteht bei verschiedenen zur Bekämpfung der Erreger eingesetzten Wirkstoffen das Problem einer Resistenzentwicklung. Unter einer Resistenz versteht man die erworbene Widerstandsfähigkeit eines Erregers gegen einen Wirkstoff. Beispielsweise führt bei resistenten Bakterienstämmen die Behandlung mit einem bestimmten oder sogar mehreren Antibiotika nicht mehr zu ihrem gewünschten Absterben oder ihrer Wachstumshemmung. Die Forschung konzentriert sich daher intensiv auch auf die Entwicklung von Therapeutika gegen resistente Erreger.Even today, however, some infectious diseases cannot be cured. In addition, there is the problem of developing resistance with various active ingredients used to combat the pathogens. Resistance is the acquired resistance of a pathogen to an active substance. For example, in the case of resistant bacterial strains, treatment with a certain or even several antibiotics no longer leads to their desired death or their growth inhibition. Research is therefore also concentrated intensively on the development of therapeutics against resistant pathogens.
Eine weitere Problematik stellen Sekundärinfektionen dar, bei denen zusätzlich zu einer zunächst vorhandenen Infektion (Primärinfektion) eine weitere Infektion mit einem anderen Erreger erfolgt. Eine solche nach einer Primärinfektion erfolgte weitere Infektion kann das Immunsystem vor große Probleme stellen und auch die Therapie und Medikation erschweren. Von besonderer Bedeutung sind Sekundärinfektionen mit Viren-, Bakterien- oder Pilzerkrankungen, wenn schon die Primärinfektion mit einer Schwächung des Immunsystems einhergeht. Es wäre daher wünschenswert, Wirkstoffe bereitzustellen, die eine gleichzeitige Bekämpfung unterschiedlicher Erreger ermöglichen.Secondary infections represent a further problem, in which, in addition to an initially present infection (primary infection), another infection with another pathogen occurs. Such a further infection after a primary infection can pose great problems for the immune system and also make therapy and medication more difficult. Secondary infections with viral, bacterial or fungal diseases are of particular importance if the primary infection is accompanied by a weakening of the immune system. It would therefore be desirable to provide active ingredients that enable different pathogens to be combated at the same time.
Vor diesem Hintergrund war es die Aufgabe der vorliegenden Erfindung, eine Möglichkeit zur Behandlung oder Vorbeugung infektiöser Erkrankungen bereitzustellen. Von besonderem Interesse ist in diesem Zusammenhang die Bereitstellung eines Mittels, das für die Behandlung unterschiedlicher infektiöser Erkrankungen eingesetzt werden kann, die durch verschiedene Erreger, wie Viren, Bakterien oder Pilze, verursacht werden.Against this background, it was the object of the present invention to provide a possibility for treating or preventing infectious diseases. Of particular interest in this context is the provision of an agent that is suitable for the treatment of different Infectious diseases can be used, which are caused by various pathogens, such as viruses, bacteria or fungi.
Überraschenderweise wurde gefunden, dass Glycosaminoglycanderivate, welche mit Hydroxymethylgruppen modifiziert wurden, eine hervorragende antiinfektive Wirkung gegenüber unterschiedlichen Arten von Erregern besitzen. Es stellte sich heraus, dass diese antiinfektive Wirkung auf die Anwesenheit von Hydroxymethylgruppen an dem Glycosaminoglycan zurückzuführen ist.Surprisingly, it has been found that glycosaminoglycan derivatives which have been modified with hydroxymethyl groups have an excellent anti-infective effect against different types of pathogens. It was found that this anti-infective effect is due to the presence of hydroxymethyl groups on the glycosaminoglycan.
Ein Gegenstand der Erfindung ist somit ein Hydroxymethylgruppen-enthaltendes Glycosaminoglycan zur Verwendung bei der Behandlung oder Vorbeugung infektiöser bzw. maligner Erkrankungen, wie in den angehängten Ansprüchen definiert.The invention thus provides a hydroxymethyl group-containing glycosaminoglycan for use in the treatment or prevention of infectious or malignant diseases, as defined in the appended claims.
Glycosaminoglycane sind linear aus sich wiederholenden modifizierten Disacchariden aufgebaute Polysaccharide. Die einzelnen Disaccharideinheiten bestehen dabei aus einer Uronsäure, die 1→3 glykosidisch mit einem Aminozucker, wie N-Acetyl-Glucosamin verbunden ist. Die Disaccharideinheiten der Ketten selbst sind 1→4 glykosidisch verknüpft. Glycosaminoglycane sind Bestandteile vieler biologischer Makromoleküle und bilden das Gerüst vieler faserbildender Stoffe. Beispiele für Glycosaminoglycane sind Hyaluronsäure, Heparin, Chondroitinsulfat, Dermatansulfat und Keratansulfat. Erfindungsgemäß werden außerdem Chitosamin und Poly-N-Acetyl-Glucosamin als Glycosaminoglycane verstanden. Vorzugsweise ist das Glycosaminoglycan eine Hyaluronsäure.Glycosaminoglycans are linear polysaccharides made up of repeating modified disaccharides. The individual disaccharide units consist of a uronic acid that is 1 → 3 glycosidically linked to an amino sugar, such as N-acetyl-glucosamine. The disaccharide units of the chains themselves are linked 1 → 4 glycosidically. Glycosaminoglycans are components of many biological macromolecules and form the framework of many fiber-forming substances. Examples of glycosaminoglycans are hyaluronic acid, heparin, chondroitin sulfate, dermatan sulfate and keratan sulfate. According to the invention, chitosamine and poly-N-acetyl-glucosamine are also understood as glycosaminoglycans. The glycosaminoglycan is preferably a hyaluronic acid.
Glycosaminoglycane werden üblicherweise aus proteinhaltigen biologischen Geweben gewonnen. Bekannt ist beispielsweise die Isolierung von Hyaluronsäure aus Hahnenkamm oder Streptokokken. Natürliche Heparine werden unter anderem aus Dünndarmmukosa vom Schwein extrahiert. Chondroitinsulfat wird größtenteils aus Knorpelgewebe von Rindern, Schweinen und Haifischen gewonnen. Außerdem können Glycosaminoglycane aus genetisch veränderten Wirtsorganismen, z.B. Bakterienzellen, erzeugt werden.Glycosaminoglycans are usually obtained from protein-containing biological tissues. For example, the isolation of hyaluronic acid from cockscomb or streptococci is known. Natural heparins are extracted from pig small intestinal mucosa, among other things. Chondroitin sulfate is largely obtained from the cartilage tissue of cattle, pigs and sharks. In addition, glycosaminoglycans can be produced from genetically modified host organisms, e.g. bacterial cells.
In der Medizin werden Hyaluronsäure und Derivate davon zur viskoelasitschen Supplementierung von Gelenken bei Arthrose, zur Auffüllung von Geweben, insbesondere der Dermis, als sogenannte "dermal filler" und zur Behandlung von entzündlichen Erkrankungen der Haut und der Schleimhäute eingesetzt. Beispielsweise beschreibt
Überraschenderweise wurde nun gefunden, dass Glycosaminoglycanderivate, in denen ein oder mehrere Aminogruppen mit Hydroxymethylgruppen substituiert sind, eine antiinfektive Wirkung besitzen und außerdem zur Behandlung maligner Erkrankungen von Körperoberflächen geeignet sind.Surprisingly, it has now been found that glycosaminoglycan derivatives, in which one or more amino groups are substituted with hydroxymethyl groups, have an anti-infective effect and are also suitable for the treatment of malignant diseases of body surfaces.
Die Disaccharideinheiten, aus welchen Glycosaminoglycane aufgebaut sind, bestehen wie oben erwähnt aus einer Uronsäure und einem Aminozucker. In den erfindungsgemäßen, mit Hydroxymethylgruppen substituierten Glycosaminoglycanderivaten ist an ein oder mehrere Strickstoffatome von Aminogruppen eine Hydroxymethylgruppe angebunden. Die erfindungsgemäßen Hydroxymethylgruppen-enthaltenden Glycosaminoglycane weisen somit charakteristische Substituenten -N(R)-CH2OH auf, wobei R ein beliebiger Rest, insbesondere H oder Acetyl, sein kann. Diese sind vorzugsweise an Aminozucker der Disaccharideinheiten des Glycosaminoglycans angebunden. Bei Glycosaminoglycanen, die den Aminozucker N-Acetylglucosamin enthalten, ist vorzugsweise die N-Acetylgruppe mit einer Hydroxymethylgruppe substituiert. Charaktertisch für diese Hydroxymethylgruppen-enthaltenden Glycosaminoglycane im Sinne der Erfindung sind -N(Acetyl)-CH2OH-Gruppen. Diese Verbindungen zeigen überraschenderweise eine besonders hohe antiinfektive Wirkung.The disaccharide units, from which glycosaminoglycans are built, consist, as mentioned above, of a uronic acid and an amino sugar. In the glycosaminoglycan derivatives according to the invention which are substituted by hydroxymethyl groups, a hydroxymethyl group is bonded to one or more nitrogen atoms of amino groups. The glycosaminoglycans containing hydroxymethyl groups according to the invention thus have characteristic substituents —N (R) —CH 2 OH, where R can be any radical, in particular H or acetyl. These are preferably bound to the aminosugars of the disaccharide units of the glycosaminoglycan. In the case of glycosaminoglycans which contain the amino sugar N-acetylglucosamine, the N-acetyl group is preferably substituted with a hydroxymethyl group. Characteristic for these hydroxymethyl group-containing glycosaminoglycans in the context of the invention are -N (acetyl) -CH 2 OH groups. These compounds surprisingly show a particularly high anti-infective effect.
Infektiöse Erkrankungen im Sinne der vorliegenden Erfindung werden durch Herpes- oder Papillomavirus verursacht. Infektiöse Erkrankungen, die nicht durch Papillom- oder Herpesviren verursacht werden, sind auch beschrieben. Infektiöse Erkrankungen, die erfindungsgemäß mittels Hydroxymethylgruppen-enthaltenden Glycosaminoglycanen behandelt oder vorgebeugt werden können, sind infektiöse Haut- oder Schleimhauterkrankungen. Zur Schleimhaut zählen dabei insbesondere auch die Oberflächen des Gastrointestinaltraktes, des Urogenitaltraktes, der Lunge und von Hohlorganen.Infectious diseases within the meaning of the present invention are caused by herpes or papillomavirus. Infectious diseases that are not caused by papilloma or herpes viruses are also described. Infectious diseases which according to the invention can be treated or prevented by means of glycosaminoglycans containing hydroxymethyl groups are infectious skin or mucous membrane diseases. The mucous membrane includes in particular the surfaces of the gastrointestinal tract, the urogenital tract, the lungs and hollow organs.
Weiterhin wird beschrieben, dass durch die Hydroxymethylgruppen-enthaltenden Gylcosaminoglycane infektiöse Erkrankungen behandelt werden können, bei denen es sich um primär virale Infektionskrankheiten mit nachfolgender Superinfektion durch Bakterien und/oder Pilze handelt, bevorzugt solcher Spezies, die gegen übliche Antibiotika resistent sind. Bei den Viren kommen DNA- und RNA-Viren infrage, bei den Bakterien sind es pathogene gram-negative und gram-positive, anaerob oder aerob wachsende Bakterien, bei den Pilzen sind es bevorzugt Sprosspilze (Hefen) und Strahlenpilze.It is also described that by the hydroxymethyl groups-containing Glycosaminoglycans infectious diseases can be treated, which are primarily viral infectious diseases with subsequent superinfection by bacteria and / or fungi, preferably those species that are resistant to common antibiotics. In the case of viruses, DNA and RNA viruses come into question; in the case of bacteria, they are pathogenic, gram-negative and gram-positive, anaerobically or aerobically growing bacteria;
Das erfindungsgemäße Mittel eignet sich auch zur Behandlung von malignen Erkrankungen der Körperoberflächen, insbesondere des Basalzellkarzinoms der Epidermis und dessen Vorstufen wie solare Keratose bzw. Morbus Bowen. Dieses wird z.B. mit einer gelförmigen Zubereitung des erfindungsgemäßen Mittels unterspritzt und wächst dann zur Oberfläche, wo es abgestoßen wird. Es wird auch beschrieben, dass andere maligne Erkrankungen adjuvant mit dem erfindungsgemäßen Mittel behandelt werden können, z. B. die Peritonealkarzinose mittels einer in die Bauchhöhle instillierten Lösung.The agent according to the invention is also suitable for the treatment of malignant diseases of the body surfaces, in particular basal cell carcinoma of the epidermis and its precursors such as solar keratosis or Bowen's disease. This is injected, for example, with a gel-like preparation of the agent according to the invention and then grows to the surface, where it is repelled. It is also described that other malignant diseases can be treated adjuvantly with the agent according to the invention, e.g. B. peritoneal carcinosis by means of a solution instilled into the abdominal cavity.
Bevorzugte Beispiele für erfindungsgemäß verwendete Glycosaminoglycane sind an Aminogruppen mit Hydroxmethyl substituierte Hyaluronsäure, Heparin, Chondroitinsulfat, Chitosamin und Poly-N-Acetyl-Glucosamin, wobei Hyaluronsäure besonders bevorzugt ist.Preferred examples of glycosaminoglycans used according to the invention are hyaluronic acid substituted on amino groups with hydroxymethyl, heparin, chondroitin sulfate, chitosamine and poly-N-acetylglucosamine, hyaluronic acid being particularly preferred.
In den erfindungsgemäßen Glycosaminoglycanderivaten sind ein oder mehrere Aminogruppen mit Hydroxymethylgruppen substituiert. Vorzugsweise liegt der Grad der Hydroxymethylierung im Bereich von 200:1 (0,5 %) bis 1:1 (100%), vorzugsweise 100:1 (1%) bis 10:1 (10 %). Mit zunehmender Hydroxymethylierung der Glycosaminoglycane nimmt überraschenderweise die antiinfektive Wirkung von Glycosaminoglycanen zu. Für Hydroxymethyl-Hyaluronsäure konnte in vitro gezeigt werden, dass insbesondere die virozide Wirkung gesteigert ist. Eine besonders bevorzugte Ausführungsform der Erfindung ist daher Hydroxymethyl-Hyaluronsäure zur Verwendung bei der Behandlung oder Vorbeugung infektiöser Erkrankungen, insbesondere viraler Erkrankungen, die durch Herpes- oder Papillomavirus verursacht sind. Beschrieben sind auch bakteriellef Erkrankungen oder Pilzerkrankungen oder Erkrankungen, die nicht durch Herpes- oder Papillomviren hervorgerufen sind.In the glycosaminoglycan derivatives according to the invention, one or more amino groups are substituted with hydroxymethyl groups. The degree of hydroxymethylation is preferably in the range from 200: 1 (0.5%) to 1: 1 (100%), preferably 100: 1 (1%) to 10: 1 (10%). With increasing hydroxymethylation of the glycosaminoglycans, surprisingly, the anti-infective effect of glycosaminoglycans increases. For hydroxymethyl-hyaluronic acid it could be shown in vitro that the virocidal effect in particular is increased. A particularly preferred embodiment of the Invention, therefore, is hydroxymethyl hyaluronic acid for use in the treatment or prevention of infectious Diseases, especially viral diseases, caused by herpes or papillomavirus. Also described are bacterial or fungal diseases or diseases that are not caused by herpes or papillomaviruses.
Im Vergleich zu bekannten antiinfektiven Mitteln, wie beispielsweise Taurolidin, besitzen die erfindungsgemäßen Hydroxymethylgruppen-enthaltenden Glycosaminoglycane eine verbesserte Gewebeverträglichkeit. Sie verbleiben länger an ihrem Wirkort, wobei die Verweildauer durch die Wahl des Molekulargewichts des verwendeten Glycosaminoglycans sowie dessen Vernetzungsgrad gesteuert werden kann. Beispielsweise bleibt Hydroxymethyl-Hyaluronsäure, abhängig von ihrem Molekulargewicht und Vernetzungsgrad, von etwa 24 Stunden bis zu sechs Monaten am Wirkort.Compared to known anti-infective agents, such as taurolidine, the hydroxymethyl group-containing glycosaminoglycans according to the invention have improved tissue compatibility. They remain at their site of action for longer, and the length of stay can be controlled through the choice of the molecular weight of the glycosaminoglycan used and its degree of crosslinking. For example, depending on its molecular weight and degree of crosslinking, hydroxymethyl-hyaluronic acid remains at the site of action for about 24 hours to six months.
Ein weiterer Vorteil ist die wesentlich erhöhte Stabilität der Verbindungen, d.h. praktisch keine Dekomposition der Verbindungen unter Abgabe von flüchtigem Formaldehyd. Gegenüber den weit gebräuchlichen antiinfektiven Antibiotika besitzen die erfindungsgemäßen modifizierten Glycosaminoglycane den Vorteil der fehlenden Resistenzentwicklung von Seiten der Erreger und eines erweiterten Erregerspektrums. Abbau und Ausscheidung erfolgen auf natürlichem Wege über spezifische Enzyme.Another advantage is the significantly increased stability of the compounds, i.e. practically no decomposition of the compounds with the release of volatile formaldehyde. Compared to the widely used anti-infective antibiotics, the modified glycosaminoglycans according to the invention have the advantage that the pathogens do not develop any resistance and that they have an expanded spectrum of pathogens. Degradation and excretion take place naturally via specific enzymes.
Zur Behandlung infektiöser Erkrankungen sind Hydroxymethylgruppen-enthaltende Glycosaminoglycane im Sinne der Erfindung sowohl in unvernetzter als auch in vernetzter Form oder als Mischungen geeignet. Besonders bevorzugt werden unvernetzte oder vernetzte Hyaluronsäure oder Mischungen davon verwendet.For the treatment of infectious diseases, glycosaminoglycans containing hydroxymethyl groups are suitable for the purposes of the invention both in uncrosslinked and in crosslinked form or as mixtures. Uncrosslinked or crosslinked hyaluronic acid or mixtures thereof are particularly preferably used.
Unvernetzte Glycosaminoglycane werden vorzugsweise ausgewählt aus (i) langkettigen Glycosaminoglycanen mit einem durchschnittlichen Molekulargewicht (Gewichtsmittel) von mindestens 200 kD und (ii) kurzkettigen Glycosaminoglycanen mit einem durchschnittlichen Molekulargewicht (Gewichtsmittel) von bis zu 50 kD oder Mischungen davon.Uncrosslinked glycosaminoglycans are preferably selected from (i) long-chain glycosaminoglycans with an average molecular weight (weight average) of at least 200 kD and (ii) short-chain glycosaminoglycans with a weight average molecular weight of up to 50 kD or mixtures thereof.
Vernetzte Glycosaminoglycane können z.B. kovalent oder nicht kovalent vernetzt sein. Die Herstellung der vernetzten Glycosaminoglycane kann an sich auf bekannte Weise erfolgen. Die kovalente Vernetzung erfolgt dabei im Allgemeinen durch Vernetzung mit bifunktionellen reaktiven Agentien, wie zum Beispiel Diepoxyoktan, BDDE, Divinylsulfon, Glutaraldehyd oder Carbodiimid, über bifunktionelle Aminosäuren, z.B. Lysin, Protamin oder Albumin. Es können z.B. aber auch Vernetzungen über eine Amid-, Ester- oder Etherbindung hergestellt werden. Weitere geeignete Reagenzien zur kovalenten Vernetzung von Glycosaminoglycanen sind Ethylenglycol- oder 1-4-Butandiol-diglycidether, Divinylsulfon, Photoquervernetzungsreagentien wie Ethyleosin, Hydrazide wie Bishydrazid, Trishydrazid und polyvalente Hydrazidverbindungen. Weiterhin können auch intra- und/oder intermolekular veresterte oder mit Hexamethylendiamin vernetzte Glycosaminoglycane eingesetzt werden. Besonders bevorzugt ist eine nicht kovalente Quervernetzung unter Verwendung mehrwertiger Metallionen, wie etwa Eisen, Kupfer, Zink, Calcium, Magnesium, Mangan, Barium und anderen chelatierenden Metallionen.Crosslinked glycosaminoglycans can, for example, be covalently or non-covalently crosslinked. The crosslinked glycosaminoglycans can be prepared in a known manner. The covalent crosslinking generally takes place by crosslinking with bifunctional reactive agents, such as diepoxyoctane, BDDE, divinyl sulfone, glutaraldehyde or carbodiimide, via bifunctional amino acids, e.g. lysine, protamine or albumin. For example, cross-links can also be established via an amide, ester or ether bond. Further suitable reagents for the covalent crosslinking of glycosaminoglycans are ethylene glycol or 1-4-butanediol diglycidether, divinyl sulfone, photocrosslinking reagents such as ethyl eosin, hydrazides such as bishydrazide, trishydrazide and polyvalent hydrazide compounds. In addition, glycosaminoglycans which are intra- and / or intermolecularly esterified or crosslinked with hexamethylenediamine can also be used. Particularly preferred is non-covalent cross-linking using polyvalent metal ions such as iron, copper, zinc, calcium, magnesium, manganese, barium and other chelating metal ions.
Bei der Anwendung ist von Bedeutung das Molekulargewicht, sowie bei vernetzten Glycosaminoglycanen der Vernetzungsgrad, der beispielsweise im Bereich von 0,1 bis 10 % liegt, ohne darauf begrenzt zu sein. Generell ist festzustellen, dass bei langkettigen Glycosaminoglycanen ein geringerer Vernetzungsgrad ausreicht, um eine gelartige Matrix zu erhalten, während bei kurzkettigen Glycosaminoglycanen ein höherer Vernetzungsgrad erforderlich ist, um vergleichbare Eigenschaften zu erhalten.In the application, the molecular weight is important, and in the case of crosslinked glycosaminoglycans the degree of crosslinking, which is, for example, in the range from 0.1 to 10%, without being limited thereto. In general, it can be stated that with long-chain glycosaminoglycans a lower degree of crosslinking is sufficient to obtain a gel-like matrix, while with short-chain glycosaminoglycans a higher degree of crosslinking is required in order to obtain comparable properties.
Das erfindungsgemäße Glycosaminoglycan kann sowohl in der Humanmedizin als auch in der Veterinärmedizin, beispielsweise zur Behandlung von Haustieren oder Nutztieren, eingesetzt werden.The glycosaminoglycan according to the invention can be used both in human medicine and in veterinary medicine, for example for the treatment of domestic animals or farm animals.
Die Verabreichung des Hydroxymethylgruppen-enthaltenden Glycosaminoglycans kann grundsätzlich auf beliebige Art und Weise erfolgen, sofern diese zur Behandlung der jeweiligen Erkrankung geeignet ist. Es ist eine systemische oder lokale Verabreichung denkbar. In vielen Fällen erfolgt eine lokale Verabreichung im Bereich der erkrankten Körperstelle.The administration of the hydroxymethyl group-containing glycosaminoglycan can in principle in any manner if this is suitable for the treatment of the respective disease. Systemic or local administration is conceivable. In many cases, local administration takes place in the area of the diseased part of the body.
Ein erfindungsgemäßes Hydroxymethylgruppen-enthaltendes Glycosaminoglycan kann zur Verwendung bei der Behandlung infektiöser Erkrankungen in Form einer pharmazeutischen Zusammensetzung vorliegen, in der ein oder mehrere Hydroxymethylgruppen-enthaltende Glycosaminoglycane in einer Menge von vorzugsweise 0,01 bis 20 Gewichtsprozent, bezogen auf die gesamte pharmazeutische Zusammensetzung, insbesondere in einer Menge von 0,01 bis 5 Gewichtsprozent und besonders bevorzugt in einer Menge von 0,01 bis 1 Gewichtsprozent enthalten sind.An inventive glycosaminoglycan containing hydroxymethyl groups can be present for use in the treatment of infectious diseases in the form of a pharmaceutical composition in which one or more glycosaminoglycans containing hydroxymethyl groups in an amount of preferably 0.01 to 20 percent by weight, based on the total pharmaceutical composition, in particular are contained in an amount of 0.01 to 5 percent by weight and particularly preferably in an amount of 0.01 to 1 percent by weight.
Als pharmazeutische Hilfsstoffe können die erfindungsgemäßen pharmazeutischen Zusammensetzungen, z.B. Mittel zur pH-Wert-Einstellung, Stabilisierungsmittel, Antioxidantien, Lösungsvermittler, penetrationsfördernde Mittel, Konservierungsmittel oder/und Gelbildner enthalten, wie sie in derartigen Zusammensetzungen üblicherweise verwendet werden. Sie werden in den in derartigen Zubereitungen üblichen Mengen verwendet.The pharmaceutical compositions according to the invention can contain as pharmaceutical auxiliaries, e.g. agents for pH adjustment, stabilizers, antioxidants, solubilizers, penetration-promoting agents, preservatives and / and gelling agents, as are usually used in such compositions. They are used in the amounts customary in such preparations.
Die erfindungsgemäßen pharmazeutischen Zusammensetzungen können gegebenenfalls neben dem Hydroxymethylgruppen-enthaltenden Glycosaminoglycan auch noch ein oder mehrere weitere pharmazeutische Wirkstoffe enthalten, die mit dem Glycosaminoglycanderivat verträglich sind. Beispiele für weitere Wirkstoffe sind Wirkstoffe zur Therapie von Hauterkrankungen (Dermatosen), Antimykotika, Antibiotika (z.B. Gentamycin, Vancomyzin, Penicillin oder Cephalosporin), Sulfonamide, Desinfektionsmittel, Hormone (z.B. Corticoide) und Hormonabkömmlinge (z.B. Cortisol), lokale Anästhetika (z.B. vom Typ des Lidocains oder Novocains), vasoaktive Substanzen zur Gefäßkonstriktion (Vermeidung von Blutungen), Adrenalin, Enzyme (wie z.B. Hyaluronidase), Interleukine, Wachstumsfaktoren (z.B. EGF, PDGF oder/und IGF), Vitamine (z.B. Vitamin D), Hautpflegemittel und/oder durchblutungsfördernde (hyperämisierende) Mittel. Die weiteren Wirkstoffe können gegebenenfalls mit dem Glycosaminoglycan assoziiert sein, z.B. durch kovalente oder nicht kovalente Wechselwirkungen.In addition to the hydroxymethyl group-containing glycosaminoglycan, the pharmaceutical compositions according to the invention can optionally also contain one or more further pharmaceutical active ingredients which are compatible with the glycosaminoglycan derivative. Examples of further active ingredients are active ingredients for the therapy of skin diseases (dermatoses), antimycotics, antibiotics (e.g. gentamycin, vancomyzin, penicillin or cephalosporin), sulfonamides, disinfectants, hormones (e.g. corticoids) and hormone derivatives (e.g. cortisol), local anesthetics (e.g. of the type of lidocaine or novocaine), vasoactive substances for vascular constriction (avoidance of Bleeding), adrenaline, enzymes (such as hyaluronidase), interleukins, growth factors (e.g. EGF, PDGF or / and IGF), vitamins (e.g. vitamin D), skin care products and / or blood circulation-promoting (hyperaemic) agents. The further active ingredients can optionally be associated with the glycosaminoglycan, for example through covalent or non-covalent interactions.
Von Bedeutung sind auch Zusatzstoffe, wie z.B. 2- oder 3-wertige Metallionen, die durch Gelatbildung quervernetzend und stabilisierend wirken können, die andererseits auch den Abbau der wirksamen Glycosaminoglycane beschleunigen können.Also of importance are additives such as divalent or trivalent metal ions, which can have a crosslinking and stabilizing effect through gelation and which, on the other hand, can also accelerate the breakdown of the effective glycosaminoglycans.
Im Gewebe erfolgt der Abbau von Glycosaminoglycanen natürlicherweise durch eine Vielzahl unterschiedlicher Enzyme oder durch Sauerstoffradikale. Hyaluronsäure wird durch Hyaluronidasen oder Sauerstoffradikale abgebaut. Daher sind weiterhin von Bedeutung Zusatzstoffe, die hemmend auf Enzyme wie Hyaluronidase einwirken (Heparin, Indometazin oder/und Salicylate) und solche, die den oxidativen Abbau im Gewebe als sogenannte Radikalfänger verhindern (Vitamine A, E oder/und C).In the tissue, glycosaminoglycans are naturally degraded by a large number of different enzymes or by oxygen radicals. Hyaluronic acid is broken down by hyaluronidases or oxygen radicals. Therefore, additives that inhibit enzymes such as hyaluronidase (heparin, indometazine and / or salicylates) and those that prevent oxidative degradation in the tissue as so-called radical scavengers (vitamins A, E and / or C) are also of importance.
In einer besonders bevorzugten Ausführungsform der Erfindung wird zur Behandlung oder Vorbeugung infektiöser Erkrankungen eine Mischung aus langkettigen Glycosaminoglycanen (≥ 200 kD) mit kurzkettigen Glycosaminoglycanen (z.B. Hexamere der repetitiven Disaccharideinheiten oder größere Einheiten bis zu 50 kD) oder auch Mischungen der vorgenannten mit quervernetzten Glycosaminoglycanen verwendet. Durch die Mischung entstehen viskose injizierbare Zubereitungen, die bevorzugt mit Injektionskanülen intradermal oder an die Grenze des dermoepidermalen Übergangs durch Injektion flächenhaft eingebracht werden. Auch das Setzen einzelner Quaddeln ist erfindungsgemäß geeignet. Den injizierbaren Glycosaminoglycan-Zubereitungen können zur Minimierung der Schmerzhaftigkeit des Einstichs die bekannten Lokalanästhetika zugesetzt werden.In a particularly preferred embodiment of the invention, a mixture of long-chain glycosaminoglycans (≥ 200 kD) with short-chain glycosaminoglycans (e.g. hexamers of the repetitive disaccharide units or larger units up to 50 kD) or mixtures of the aforementioned with cross-linked glycosaminoglycans is used to treat or prevent infectious diseases . The mixture creates viscous injectable preparations, which are preferably introduced intradermally with injection cannulas or by injection over a large area at the border of the dermoepidermal transition. The placement of individual wheals is also suitable according to the invention. The known local anesthetics can be added to the injectable glycosaminoglycan preparations to minimize the painfulness of the puncture.
Eine weitere besonders bevorzugte Ausführungsform sind Mischungen aus quervernetzten und nicht quervernetzten Glycosaminoglycanen.Another particularly preferred embodiment are mixtures of crosslinked and non-crosslinked glycosaminoglycans.
Anstelle der Injektionstechnik mit Kanülen lassen sich die erfindungsgemäßen Zubereitungen äußerst wirksam auch durch Druckinjektion anwenden. Dieses Verfahren zeichnet sich durch weitgehende Schmerzfreiheit aus.Instead of the injection technique with cannulas, the preparations according to the invention can also be used extremely effectively by pressure injection. This procedure is characterized by extensive freedom from pain.
Weitere erfindungsgemäße Zubereitungen des Wirkstoffs sind wässrige Lösungen oder Emulsionen zur intravenösen Applikation oder zur Instillation in Körperhöhlen oder Hohlorgane.Further preparations according to the invention of the active ingredient are aqueous solutions or emulsions for intravenous administration or for instillation into body cavities or hollow organs.
Weiterhin können die erfindungsgemäßen Zubereitungen auch topisch, d.h. oberflächlich auf die Haut in Form von Salben, Cremes, Lotionen, Gelen, Sprays, Tinkturen, Shampoos, Oklusivfolien aufgebracht werden. Eine besondere Zubereitungsform im Sinne der Erfindung ist eine trockene Glycosaminoglycan-Zubereitung in Form eines Puders, welches insbesondere zur Behandlung nässender Ekzeme Verwendung findet. Auch das Einbringen der Wirkstoffe in mikroverkapselter Form bzw. in Form von Liposomen ist Gegenstand der Erfindung. Soweit Schleimhäute der Atemwege von einer infektiösen Erkrankung betroffen sind, kann eine Behandlung mit den erfindungsgemäßen Hydroxymethylgruppen-enthaltenden Glycosaminoglycanen auch unter Anwendung eines Aerosols als Inhalationslösung erfolgen.Furthermore, the preparations according to the invention can also be applied topically, i.e. superficially, to the skin in the form of ointments, creams, lotions, gels, sprays, tinctures, shampoos, and occlusive films. A special preparation form within the meaning of the invention is a dry glycosaminoglycan preparation in the form of a powder, which is used in particular for the treatment of weeping eczema. The invention also relates to the introduction of the active ingredients in microencapsulated form or in the form of liposomes. As far as mucous membranes of the respiratory tract are affected by an infectious disease, treatment with the glycosaminoglycans according to the invention containing hydroxymethyl groups can also be carried out using an aerosol as an inhalation solution.
Die Herstellung einer erfindungsgemäßen Zusammensetzung kann auf eine, für die Herstellung derartiger Zusammensetzungen an sich übliche, allgemein bekannte Weise, erfolgen. Dabei ist die Reihenfolge der Vermischung der einzelnen Bestandteile in der Regel nicht kritisch.A composition according to the invention can be produced in a generally known manner which is customary per se for the production of such compositions. The order in which the individual components are mixed is generally not critical.
Die Art, Dosis und Häufigkeit der Verabreichung der erfindungsgemäßen Zusammensetzung sowie die Beschaffenheit (z.B. Viskosität, Vernetzungsgrad, Wirkstoffgehalt etc.) richten sich insbesondere nach der Art und Schwere der Erkrankung sowie nach dem Alter des Patienten und dem Ort und der Art der Applikation, z.B. dem Zustand und der Empfindlichkeit der betroffenen Körperstellen. Werden die erfindungsgemäßen Zusammensetzungen in Form topisch applizierbarer Zubereitungen verabreicht, so entspricht die Verabreichung in der Regel den für derartige Zusammensetzungen üblichen Bedingungen.The type, dose and frequency of administration of the composition according to the invention as well as the nature (e.g. viscosity, Degree of cross-linking, active ingredient content etc.) depend in particular on the type and severity of the disease as well as on the age of the patient and the location and type of application, e.g. the condition and sensitivity of the affected parts of the body. If the compositions according to the invention are administered in the form of preparations that can be applied topically, the administration generally corresponds to the conditions customary for such compositions.
Die Art der Behandlung und die Häufigkeit der Applikation richtet sich insbesondere auch nach dem individuellen Ansprechen der zu behandelnden Personen. Vorzugsweise erfolgt eine Applikation von Gelen oder Lösungen in Abständen von mehreren Tagen bis zu 1 oder 2 Monaten, insbesondere ca. 1-2 Wochen.The type of treatment and the frequency of application depends in particular on the individual response of the person to be treated. Gels or solutions are preferably applied at intervals of several days up to 1 or 2 months, in particular about 1-2 weeks.
Die Erfindung beinhaltet auch Mischungen eines Hydroxymethylgruppen-enthaltenden Glycosaminoglycans mit anderen Glycosaminoglycanen in vernetzter oder/und nicht vernetzter Form. Zu möglichen Kombinationen und Quervernetzungsmöglichkeiten wird Bezug genommen auf
Die Herstellung eines Hydroxymethylgruppen-enthaltenden Glycosaminoglycans umfasst vorzugsweise die Schritte:
- (i) Bereitstellen von Glycosaminoglycan und
- (ii) Substituieren ein oder mehrerer Aminogruppen des Glycosaminoglycans mit Hydroxymethylgruppen.
- (i) providing glycosaminoglycan and
- (ii) Substituting one or more amino groups of the glycosaminoglycan with hydroxymethyl groups.
Als Glycosaminoglycan Ausgangsprodukt in Schritt (i) wird vorzugsweise Hyaluronsäure, Heparin, Chondroitinsulfat, Chitosamin oder Poly-N-Acetylglucosamin verwendet.The glycosaminoglycan starting product in step (i) is preferably Hyaluronic acid, heparin, chondroitin sulfate, chitosamine or poly-N-acetylglucosamine are used.
In einer besonders bevorzugten Ausführungsform ist das Glycosaminoglycan in Schritt (i) aus einer biologischen Quelle isoliert oder biotechnologisch gewonnen, insbesondere aus Hahnenkamm oder Bakterien, wie B. subtilis oder Streptokokken-Kulturen.In a particularly preferred embodiment, the glycosaminoglycan in step (i) is isolated from a biological source or obtained biotechnologically, in particular from cockscomb or bacteria such as B. subtilis or streptococcal cultures.
Die Gewinnung des Glycosaminoglycans aus einer biologischen Quelle oder aus Bakterien kann in Anwesenheit von Formaldehyd oder einem anderen Hydroxymethylgruppendonor erfolgen. Das gereinigte Glycosaminoglycan aus Schritt (i) liegt dann beispielsweise als wässrige Lösung, als Präzipitat oder als Hydrogel vor.The glycosaminoglycan can be obtained from a biological source or from bacteria in the presence of formaldehyde or another hydroxymethyl group donor. The purified glycosaminoglycan from step (i) is then available, for example, as an aqueous solution, as a precipitate or as a hydrogel.
In Schritt (ii) wird das Glycosaminoglycan dann durch chemische Behandlung mit Hydroxymethylgruppen substituiert. Schritt (ii) kann zusammen mit Schritt (i) oder danach durchgeführt werden. Schritt (ii) kann beispielsweise die Umsetzung des Glycosaminoglycans mit Formaldehyd oder einem unter den Reaktionsbedingungen Formaldehyd freisetzenden Mittel, wie etwa Taurolidin, umfassen. Ein bevorzugtes Verfahren zur Einführung von Hydroxymethylgruppen in das Glycosaminoglycan (z.B. Hyaluronsäure) verwendet Taurolidin in 1-2 %iger Lösung. Glycosaminoglycan wird dabei mit der Taurolidinlösung im Verhältnis 1 mg auf 1 ml versetzt und für 24 h unter Verschluss oder unter einer Gasatmosphäre von 1-100 bar inkubiert. Vorteil dieses Vorgehens ist, dass Taurolidin selbst sehr viel weniger toxisch ist als Formaldehyd.In step (ii) the glycosaminoglycan is then substituted with hydroxymethyl groups by chemical treatment. Step (ii) can be carried out together with step (i) or afterwards. Step (ii) can comprise, for example, the reaction of the glycosaminoglycan with formaldehyde or an agent which releases formaldehyde under the reaction conditions, such as taurolidine. A preferred method of introducing hydroxymethyl groups into the glycosaminoglycan (e.g. hyaluronic acid) uses taurolidine in a 1-2% solution. Glycosaminoglycan is mixed with the taurolidine solution in a ratio of 1 mg to 1 ml and incubated for 24 hours under lock and key or under a gas atmosphere of 1-100 bar. The advantage of this approach is that taurolidine itself is much less toxic than formaldehyde.
Anschließend kann das mit Hydroxymethylgruppen modifizierte Glycosaminoglycan in einem weiteren Schritt (iii) aufgereinigt werden. Überschüssiges Formaldehyd bzw. Reste von Formaldehyd-freisetzenden Reagenzien aus Schritt (ii) werden dabei entfernt. Die Aufreinigung kann beispielsweise durch Fällen mit z.B. Alkoholen oder Salzen, durch Chromatographieverfahren, Dialyseverfahren, Vakuumextraktion und/oder Gefriertrocknen erfolgen.The glycosaminoglycan modified with hydroxymethyl groups can then be purified in a further step (iii). Excess formaldehyde or residues of formaldehyde-releasing reagents from step (ii) are removed. The purification can, for example, by precipitation with, for example, alcohols or salts, by chromatography processes, dialysis processes, vacuum extraction and / or Freeze-drying can be carried out.
Optional erfolgt anschließend ein weiterer Schritt (iv), in dem das mit Hydroxymethylgruppen substituierte Glycosaminoglycan quervernetzt wird. Grundsätzlich kann auch zuerst die Quervernetzung vorgenommen werden und dann die Einführung von Hydroxymethylgruppen. Die Quervernetzung kann, wie vorstehend beschrieben, nach im Stand der Technik bekannten Verfahren erfolgen. In einer besonders bevorzugten Ausführungsform erfolgt in Schritt (iv) eine Quervernetzung mit ein oder mehreren weiteren Glycosaminoglycanen, die optional selbst an Aminogruppen mit Hydroxymethylgruppen substituiert sein können. Beispiele für solche weiteren optional mit Hydroxymethylgruppen modifizierten Glycosaminoglycane sind Heparin, Chondroitinsulfat, Chitosamin und Poly-N-Acetylglucosamin.A further step (iv) is then optionally carried out, in which the glycosaminoglycan substituted with hydroxymethyl groups is crosslinked. In principle, the crosslinking can also be carried out first and then the introduction of hydroxymethyl groups. The crosslinking can, as described above, take place according to methods known in the prior art. In a particularly preferred embodiment, crosslinking takes place in step (iv) with one or more further glycosaminoglycans, which can optionally themselves be substituted on amino groups with hydroxymethyl groups. Examples of such further glycosaminoglycans optionally modified with hydroxymethyl groups are heparin, chondroitin sulfate, chitosamine and poly-N-acetylglucosamine.
In einer weiteren bevorzugten Ausführungsform der Erfindung wird ein Hydroxymethylgruppen-enthaltendes Glycosaminoglycan anschließend mit ein oder mehreren weiteren Wirkstoffen und/oder Zusatzstoffen kombiniert. Beispiele für solche weiteren Wirkstoffe und Zusatzstoffe sind vorstehend erläutert.In a further preferred embodiment of the invention, a glycosaminoglycan containing hydroxymethyl groups is then combined with one or more further active ingredients and / or additives. Examples of such further active ingredients and additives are explained above.
Ein weiterer Aspekt der Erfindung betrifft eine Kombination von Hydroxymethylgruppen-enthaltendem Glycosaminoglycan mit Taurolidin, z.B. mit einer Taurolidin-Lösung, z.B. einer 1-2 % (w/v) Taurolidinlösung. Als Glycosaminoglycan wird dabei vorzugsweise Hyaluronsäure verwendet, wobei das Molekulargewicht der Hyaluronsäure beispielsweise zwischen 100.000 und 10.000.000 Dalton liegen kann.Another aspect of the invention relates to a combination of hydroxymethyl group-containing glycosaminoglycan with taurolidine, for example with a taurolidine solution, for example a 1-2% (w / v) taurolidine solution. Hyaluronic acid is preferably used as the glycosaminoglycan, the molecular weight of the hyaluronic acid being, for example, between 100,000 and 10,000,000 Daltons.
Eine erfindungsgemäße Zusammensetzung kann vorzugsweise in gasdichter Verpackung, wie z.B. einer Glasspritze, gelagert werden und zeichnet sich durch eine erhöhte antiinfektive und prolongierte Wirkung sowie durch eine verbesserte Gewebeverträglichkeit aus.A composition according to the invention can preferably be stored in gas-tight packaging, such as a glass syringe, and is characterized by an increased anti-infective and prolonged effect as well as improved tissue compatibility.
Weiterhin wird ein Verfahren zur Behandlung einer bakteriellen Entzündung des Kniegelenks beschrieben, wobei das Hydroxmethylgruppen-enthaltende Glycosaminoglycan nach einem der Ansprüche 1-8, bevorzugt als Gel instilliert oder als Spüllösung eingesetzt wird.Furthermore, a method for treating bacterial inflammation of the knee joint is described, wherein the hydroxymethyl group-containing glycosaminoglycan according to one of claims 1-8, preferably instilled as a gel or used as a rinsing solution.
Fermentativ gewonnene HA aus Streptococcus equi wird in Taurolidin-Lösung 2% gelöst und 12 Std. bei 40 °C gehalten. Danach wird überschüssige Flüssigkeit durch Filtration abgeschieden und verbliebene Flüssigkeit durch Vakuumtrocknung entfernt. Das erhaltene Produkt wird dann in physiologischer NaCI-Lösung gelöst und der pH-Wert der Lösung wird mit 1 % NaOH auf 10 eingestellt. Sodann wird BDDE zugesetzt bis zu einer Konzentration von 0,2 %. Der Ansatz wird bei 40 °C für 4 Std. inkubiert. Danach wird mit Na-Acetat der pH-Wert des Ansatzes auf 7,4 eingestellt und dieser für weitere 24 Std. bei 70 Grad Celsius gehalten. Nach Abkühlung auf Raumtemperatur kann die Weiterverarbeitung des Ansatzes zum antiinfektiven Endprodukt, z.B. Augengel, erfolgen.HA obtained by fermentation from Streptococcus equi is dissolved in 2% taurolidine solution and kept at 40 ° C. for 12 hours. Thereafter, excess liquid is separated off by filtration and remaining liquid is removed by vacuum drying. The product obtained is then dissolved in physiological NaCl solution and the pH of the solution is adjusted to 10 with 1% NaOH. BDDE is then added to a concentration of 0.2%. The mixture is incubated at 40 ° C. for 4 hours. The pH of the batch is then adjusted to 7.4 with Na acetate and kept at 70 degrees Celsius for a further 24 hours. After cooling to room temperature, the batch can be further processed into the anti-infective end product, eg eye gel.
Streptococcus equi Spezies werden in Fermentatoren in einer CO2 angereicherten anaeroben Atmosphäre gezüchtet. Nach Beendigung des Wachstums bzw. der Vermehrung wird der Nährlösung Formaldehyd in konzentrierter Form zugegeben, sodass die Bakterien absterben. Streptococcus equi species are grown in fermenters in a CO 2 enriched anaerobic atmosphere. After growth or reproduction has ended, formaldehyde is added in concentrated form to the nutrient solution so that the bacteria die.
Die Lösung wird sodann zentrifugiert und der Überstand abgezogen. Das erhaltene Material wird mit verdünnter NaOH versetzt und für 4 Std. geschüttelt. Die Lösung wird danach neutralisiert und ultrafiltiert. Die erhaltene Lösung kann mit Alkohol behandelt und die gelöste HA ausgefällt und getrocknet werden. Es liegt damit ein erfindungsgemäßes Produkt vor, welches je nach beabsichtigter Anwendung weiter verarbeitet werden kann.The solution is then centrifuged and the supernatant drawn off. The material obtained is mixed with dilute NaOH and shaken for 4 hours. The solution is then neutralized and ultrafiltered. The received Solution can be treated with alcohol and the dissolved HA precipitated and dried. There is thus a product according to the invention which can be further processed depending on the intended application.
100 ml einer 2 %igen Hyaluronsäurelösung werden mit 100 ml einer 2 %igen Taurolinlösung gemischt und unter Luftabschluss in einer Glasflasche aufbewahrt. Die Lösung kann bei Bedarf über ein Schlauch- bzw. Kathetersystem in die Bauchhöhle oder in die Harnblase instilliert werden.100 ml of a 2% hyaluronic acid solution are mixed with 100 ml of a 2% taurolin solution and stored in a glass bottle in the absence of air. If necessary, the solution can be instilled into the abdominal cavity or the urinary bladder through a tube or catheter system.
Claims (15)
- Hydroxymethyl-group-containing glycosaminoglycan in which one or more amino groups are substituted with hydroxymethyl, for use in the treatment or prevention of viral infectious or malignant skin or mucosal diseases, wherein the viral infectious diseases are caused by herpes viruses or papillomaviruses, and wherein the malignant diseases are basal cell carcinoma of the epidermis and its precursors, and wherein glycosaminoglycans are linear polysaccharides composed of repeating modified disaccharides, wherein the disaccharide units of the chains are themselves linked 1→4 glycosidically.
- Hydroxymethyl-group-containing glycosaminoglycan according to claim 1 for use according to claim 1,
characterised in that
the precursors of basal cell carcinoma of the epidermis are solar keratosis and Bowen's disease. - Hydroxymethyl-group-containing glycosaminoglycan according to either claim 1 or claim 2 for use according to either claim 1 or claim 2,
characterised in that
the glycosaminoglycan is selected from hyaluronic acid, heparin, chondroitin sulfate, chitosamine and poly-N-acetyl glucosamine, preferably hyaluronic acid in which one or more amino groups are substituted with hydroxymethyl. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
characterised in that
the degree of hydroxymethylation is in the range from 200:1 (0.5%) to 1:1 (100%), preferably 100:1 (1%) to 10:1 (10%). - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
for local administration, in particular for intradermal administration, for administration at the border of the dermo-epithelial junction or for topical administration. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
characterised in that(a) the hydroxymethyl-group-containing glycosaminoglycan is present in uncrosslinked form, in particular selected from(i) long-chain glycosaminoglycans having an average molecular weight (weight average) of at least 200 kD and(ii) short-chain glycosaminoglycans having an average molecular weight (weight average) of up to 50 kDor mixtures thereof, or(b) in that the hydroxymethyl-group-containing glycosaminoglycan is present in crosslinked form, in particular in that the degree of crosslinking is in the range from 0.1% to 10%, or(c) in that the hydroxymethyl-group-containing glycosaminoglycan is present as a mixture of uncrosslinked and crosslinked glycosaminoglycans. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of claims 1 to 6,
characterised in that
it is present as an injectable preparation, ointment, cream, lotion, gel, spray, tincture, rinsing or infusion solution, drop solution, shampoo, occlusive film, powder or inhalable preparation, in particular an aerosol. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of claims 1 to 7,
characterised in that
the infectious skin or mucosal disease is selected from diseases of body surfaces, the gastrointestinal tract, the knee, the urogenital tract and the lungs. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
in human or veterinary medicine. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
characterised in that
the hydroxymethyl-group-containing glycosaminoglycan is present in combination with at least one inhibitor of glycosaminoglycan degradation, the inhibitor of glycosaminoglycan degradation being selected in particular from heparin, indometazine, salicylates, radical scavengers, such as vitamin A, C or E, and mixtures thereof. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims,
characterised in that
the hydroxymethyl-group-containing glycosaminoglycan is present in combination with one or more further glycosaminoglycans in crosslinked or uncrosslinked form, which further glycosaminoglycans can optionally contain hydroxymethyl groups, the further glycosaminoglycans being selected in particular from heparin, chondroitin sulfate, chitosamine and poly-N-acetyl glucosamine. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims, for use in particular according to any of the preceding claims,
characterised in that
the hydroxymethyl-group-containing glycosaminoglycan is present in combination with taurolidine. - Hydroxymethyl-group-containing glycosaminoglycan according to any of the preceding claims for use according to any of the preceding claims in the treatment or prevention of infectious diseases of the eye, in particular of the conjunctiva or cornea of the eye such as conjunctivitis,
wherein the hydroxymethyl-group-containing glycosaminoglycan according to any of claims 1-7 is preferably instilled as a gel or used as a rinsing solution. - Method for producing a hydroxymethyl-group-containing glycosaminoglycan, comprising the steps of:(i) providing glycosaminoglycan and(ii) substituting one or more amino groups of the glycosaminoglycan with hydroxymethyl groups,the glycosaminoglycan being selected in particular from hyaluronic acid, heparin, chondroitin sulfate, chitosamine and poly-N-acetyl glucosamine.
- Method according to claim 14,(a) wherein the glycosaminoglycan in step (i) is isolated from a biological source or obtained biotechnologically, in particular from cockscomb or transgenic bacteria such as B. subtilis or streptococcal cultures, and/or(b) wherein step (ii) comprises reacting glycosaminoglycan with formaldehyde or an agent which releases formaldehyde under the reaction conditions, such as taurolidine, and/or(c) further comprising the step of
(iii) purifying the hydroxymethyl-group-substituted glycosaminoglycan, in particular by precipitation using e.g. alcohols or salts, chromatography processes, dialysis processes, vacuum extraction or freeze-drying, and/or(d) further comprising the step of
(iv) crosslinking the hydroxymethyl-group-substituted glycosaminoglycan, wherein step (iv) in particular comprises crosslinking with one or more other glycosaminoglycans, which themselves can also be modified with hydroxymethyl groups at amino groups.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE102011077393A DE102011077393A1 (en) | 2011-06-10 | 2011-06-10 | Antiinfective agent |
| PCT/EP2012/060942 WO2012168462A1 (en) | 2011-06-10 | 2012-06-08 | Antiinfective composition |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| EP2717885A1 EP2717885A1 (en) | 2014-04-16 |
| EP2717885B1 true EP2717885B1 (en) | 2021-08-11 |
Family
ID=46210287
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP12726137.8A Active EP2717885B1 (en) | 2011-06-10 | 2012-06-08 | Antiinfective composition |
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|---|---|
| US (1) | US10022394B2 (en) |
| EP (1) | EP2717885B1 (en) |
| DE (1) | DE102011077393A1 (en) |
| WO (1) | WO2012168462A1 (en) |
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|---|---|---|---|---|
| CN105039193B (en) * | 2015-01-27 | 2016-08-17 | 安徽正方生物科技有限公司 | A kind of fermentable produces bacterial strain and the method for glucosamine |
| EP3344256B1 (en) * | 2015-08-31 | 2020-08-05 | CorMedix Inc. | Compositions for the treatment of joints |
| US20190192552A1 (en) * | 2017-12-21 | 2019-06-27 | Cormedix Inc. | Pharmaceutical compositions and methods for treating keloids, hypertrophic scars and wounds, and for providing improved skin care |
| US20230122776A1 (en) | 2020-03-27 | 2023-04-20 | Johannes Reinmüller | Antiviral agent |
Citations (3)
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| DE10209966A1 (en) * | 2001-11-12 | 2003-05-22 | Johannes Reinmueller | Pharmaceutical applications of hyaluronic acid preparations |
| WO2003041723A1 (en) * | 2001-11-12 | 2003-05-22 | Reinmueller Johannes | Pharmaceutical applications of hyaluronic acid preparations |
| WO2005067944A1 (en) * | 2004-01-14 | 2005-07-28 | Reinmueller Johannes | Agent for treating inflammatory diseases |
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| LU77562A1 (en) * | 1977-06-17 | 1979-03-26 | Ciba Geigy Ag | METHOD FOR PRODUCING NEW PHARMACEUTICAL PREPARATIONS |
| US5099013A (en) | 1985-03-12 | 1992-03-24 | Biomatrix, Inc, | Hylan preparation and method of recovery thereof from animal tissues |
| US4713448A (en) * | 1985-03-12 | 1987-12-15 | Biomatrix, Inc. | Chemically modified hyaluronic acid preparation and method of recovery thereof from animal tissues |
| IT1230582B (en) * | 1988-10-21 | 1991-10-28 | Opocrin S P A Lab Farmabiologi | DERMATAN SULPHATE AND HEPARIN OILGOSACCHARID WITH ANTI-THEROSCLEROTIC ACTIVITIES |
| US5114957A (en) * | 1990-05-08 | 1992-05-19 | Biodor U.S. Holding | Tocopherol-based antiviral agents and method of using same |
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| US5250519A (en) * | 1991-03-29 | 1993-10-05 | Glycomed Incorporated | Non-anticoagulant heparin derivatives |
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Also Published As
| Publication number | Publication date |
|---|---|
| US10022394B2 (en) | 2018-07-17 |
| EP2717885A1 (en) | 2014-04-16 |
| US20140113881A1 (en) | 2014-04-24 |
| WO2012168462A1 (en) | 2012-12-13 |
| DE102011077393A1 (en) | 2012-12-13 |
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